The focus of the proposed research will be on glutamate (Glu) and certain structural analogs, the excitotoxic amino acids, which are so-called because of their neuroexcitatory and neurotoxic properties. Accumulating evidence suggests that some of these agents, particularly Glu and aspartate (Asp) which are abundantly present in brain, may be natural excitatory transmitters. The ability of these agents, when administered systematically, to penetrate circumventricular organ (CVO) regions of brain and either stimulate (excite) or kill CVO neurons makes them useful tools for studying the neuroendocrine or other functioal roles of CVO neurons. Several of the excitotoxic amino acids, especially the more potent analogs such as kainic acid and N-methyl aspartate, hold promise as research tools for producing axon-sparing lesions when introduced directy into various region of brain. The applicant proposes to continue studying the mechanism(s) of neurotoxicity of these compounds and, in particular, will attempt to clarify the possibility that they exert their toxic activities through synaptic receptors that use Glu or Asp as transmitter. Other objectives of the proposed research include developing new research applications for the excitotoxic amino acids, improving those already developed and exploring the hypothesis that excitotoxins play a role in human neurodegenerative disorders. Morphological, neurochemical, neuropharmacological and neurotoxicological approaches involving light and electron microscopy, autoradiography, quantitative histochemistry and radioimmunoassay will be employed.